The long-term goals of this project are to increase our understanding of the neural processes that underlie alcoholism, thereby accelerating development of effective treatment strategies. Individuals susceptible to alcoholism show a characteristic progression from intermittent social use of alcohol to compulsive drinking and frequent relapse, despite severe social and economic consequences. Thus, these individuals differ from the general population in their response to repeated alcohol exposure. Examination of neuroadaptive responses that develop from such drug exposure will, therefore, be valuable in shedding light on the neural mechanisms underlying this disease. The proposed 5-year project will examine sensitization, and conditioned responses to stimuli paired with drug administration, two neuroadaptive responses that have been accorded central roles in contemporary theories of drug abuse. Specifically, the experiments will assess the conditions under which sensitization develops, the neuropharmacological bases of sensitization, the contribution of conditioning processes to sensitization, and the impact of sensitization and conditioned responses on the behavioral effects of alcohol. Changes in locomotor activity in DBA/2J mice will be used as the experimental model. Initial experiments will examine the influence of alcohol dose and number of drug exposures on acquisition of sensitization. The neuropharmacological bases of sensitization will then be assessed by manipulating selected neurotransmitter systems using specific CNS lesions, dopamine and glutamate antagonists, and GABA agonists. Manipulations that alter sensitization will be examined further in studies that assess the contribution of conditioning processes to sensitization. Additional experiments will assess the impact of sensitization and conditioned responses on the rewarding effects of alcohol, and development of cross-sensitization between alcohol and other drugs. Finally, several mouse populations will be screened for development of sensitization in order to identify a second population with which parallel experiments can be conducted in the future. Such studies will increase the generality of findings in DBA/2J mice. The studies proposed in this application will provide valuable new information regarding the neural mechanisms underlying neuroadaptive responses to alcohol and the impact of these responses on the rewarding effects of alcohol.